The goal of this project is to develop improved pharmacologic approaches to the treatment of neuropsychiatric disease based on an understanding of the relation between transmmitter mechanisms and psychomotor function. These integrated clinical and preclinical efforts are focused on the dopamine system and closely interacting pathways in relation to extrapyramidal and dementing disorders. 1. Positron emission tomography - fluorodeoxyglucose studies of Alzheimer's disease revealed diffuse cortical hypometabolism, most marked in the parieto-temporal association area; the amount of cortical abnormality correlated with the degree of dementia; initial studies of Tourette syndrome suggested a characteristic pattern of corticval and basal ganglia dysfunction; the cortical localization of several cognitive functions, including aspects of language and visual-spatial task performance, have been mapped. 2. Dopamine agonist therapy with bromocriptine was found to improve dystonia in most patients; selective dopamine autoreceptor stimulation by EMD 23448 had no effect on Huntington's chorea; beta-adrenergic blockade with nadolol significantly reduced both resting and action tremor in parkinsonian patients. 3. GABA system abnormalities in Alzheimer's disease were documented in a cerebrospinal fluid study and the GABA agonist, THIP, was evaluated in the rigid variant of Huntington's disease. 4. Cholecystokinin (CCK), a neuropeptide located in some dopamine neurons, was found to be metabolized in rat brain to fragments which bind to central CCK receptors and exert independent activity; in the experimental animal systemic administration of CCK-8 significantly influenced central dopamine metabolism, motor function, and operant behavior. Clinical trials of a CCK-8 analog in patients with dyskinesias has been initiated.